Methylene Transfer Reaction Research Articles

A Case for Mechanisms

AbstractA case study in the (re)discovery of a non‐diazo, catalytic, electrophilic cyclopropanation reaction is presented to illustrate the role of mechanistic concepts in chemical innovation. The specific instance also highlights how specific personalities interacted in the report, retraction, and reconsideration of a novel methylene transfer reaction. The case study ends with a series of lessons learned, which generalize the findings from the specific case.

Methylene-transfer reactions of benzylium/tropylium ions with neutral toluene studied by means of ion-trap mass spectrometry

The ion–molecule reactions of C7H7+ ions with neutral toluene are investigated in an ion-trap mass spectrometer, which is shown to be suitable instrumentation for kinetic studies, although the absolute rate constant can only be derived with difficulties. The benzylium ions C6H5CH2+ undergo a formal CH2+ transfer with toluene to afford the corresponding xylenium ions, CH3–C6H4–CH2+, whereas the tropylium ions c-C7H7+ do not react. The results for the parent compound C7H7+ are complemented with data for the tert-butyl derivative generated by collision-induced dissociation of the corresponding p-(tert-butyl)benzyl pyridinium ion. For the tert-butyl substituted ion, the benzylium/tropylium dichotomy exists in a similar manner in that reactive and non-reactive fractions are observed, of which the former is assigned to the benzylium structure on the basis of infrared-multiphoton dissociation spectra.

Lanthanum(III)-Catalyzed Cyclopropanation

A lanthanum(III) triflate catalyzed cyclopropanation protocol involving the methylene transfer from epoxides to olefins is described. The resulting aldehydes and ketones are obtained in good yield and the reactions proceed with high ­diastereoselectivity. Furthermore, enantioenriched cyclopropanes can be obtained following asymmetric epoxidation and methylene transfer reactions.

Methylene Transfer from SnMe Groups Mediated by a Rhodium(I) Pincer Complex: SnC, CC, and CH Bond Activation

The PCP-Rh(I) complex 1a based on the [1,3-phenylenebis(methylene)]bis(diisopropylphosphine) ligand reacts with [diazo(phenyl)methyl]trimethylstannane (2) at room temperature to give novel pincer-type phenyl(dimethylstannyl)methylene]hydrazinato complex 3a. The reaction sequence involves a unique combination of Sn-C bond cleavage, C-C bond formation, C-H activation and intramolecular deprotonation of a rhodium hydride intermediate, which results in methylene transfer from an SnMe group to the pincer system and PCP-chelate expansion. A methylene-transfer reaction was also demonstrated with tetramethyltin as the methylene source in the presence of KOC(CH(3))(3) at room temperature. The resulting unstable "chelate-expanded" Rh(I) complex [(C(10)H(5)(CH(2)PiPr(2))(2))(CH(2))Rh(L)] (L=N(2), THF; 4a) was isolated as its carbonyl derivative 5a. Heating 4a in benzene yielded an equimolar amount of toluene and 1a, which demonstrates the ability of the Rh(I) pincer complex to extract a methylene group from an unactivated alkyl tin substrate and transfer it, via C-C followed by C-H activation, to an arene. Use of fluorobenzene resulted in formation of fluorotoluene. Catalytic methylene-group transfer mediated by 1a was not possible, because of formation of o-xylylene complex 8 under the reaction conditions. Steric parameters play a decisive role in the reactivity with tin compounds; while iPrP derivative 1 a underwent facile reactions, tBuP complex 1b was inert.

Carbene Complexes of Nonmetals

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cover Picture: Cycloadditions and Methylene Transfer in Reactions of Substituted Thiocarbonyl S‐Methylides with Thiobenzophenone: A Computational Study (Eur. J. Org. Chem. 8/2005)

AbstractThe cover picture shows the potential energy diagram of methylene transfer from 4,4,5,5‐tetramethylcyclopentanethione S‐methylide to thiobenzophenone via a biradical intermediate which wins over a possible formation of regioisomeric cycloadducts. Methylene transfer reactions together with 1,3‐dipolar cycloadditions of other thiocarbonyl S‐methylides to thiones are described by R. Huisgen et al. on p. 1519 ff. DFT calculations on the mechanism of these reactions, concerted or stepwise, are reported by R. Sustmann et al. on p. 1505 ff.

Cycloadditions and Methylene Transfer in Reactions of Substituted Thiocarbonyl S‐Methylides with Thiobenzophenone: A Computational Study

AbstractRegiochemistry and methylene transfer reactions in cycloadditions of aliphatic thiocarbonyl S‐methylides and thiobenzophenone are analyzed by ab initio [(U)HF/3‐21G*] and DFT calculations [(U)B3LYP/6‐31G*//(U)HF/3‐21G* and (U)B3LYP/6‐31G*]. The formation of regioisomeric 1,3‐dithiolanes is explained by the competition of concerted (2,4‐substituted 1,3‐dithiolane) and stepwise cycloaddition via C,C‐biradicals (4,5‐substituted 1,3‐dithiolane). Aliphatic thiocarbonyl S‐methylides with sterically demanding substituents undergo substantial methylene transfer in the reaction with thiobenzophenone. This process involves dissociation of the C,C‐biradical intermediate with liberation of thiobenzophenone S‐methylide which, in turn, combines with a second molecule of thiobenzophenone. Calculated activation parameters for the different processes are in agreement with the experimental observations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Carbene Complexes of Nonmetals

AbstractElectrophilic carbenes accept a variety of n‐ and π‐donors. The products range from persistent ylides to matrix‐isolated xenon complexes. Ylides can be viewed as carbene complexes if they regenerate carbenesthermallyor undergoconcertedmethylene transfer reactions. According to these definitions, the present review focuses on oxonium and iodonium ylides. Transient π‐complexes appear to be involved in addition reactions of carbenes with arenes (but not with alkenes). Nucleophilic carbenes form adducts with Lewis acids which are, for the most part, stable and have been well characterized structurally. Only recently attention has been directed to reversible systems. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Mechanism of the Methylene Transfer Reaction. C−C Activation and Reductive Elimination in One System. A DFT Study

DFT calculations were employed to investigate the methylene transfer reaction mechanism in a model system related to the experimental Rh/PCP ligand system previously reported by us. The computationally established mechanism is in accordance with the experimental results. It was found to be a C−C reductive elimination/C−C oxidative addition sequence in which the C−C reductive elimination is the rate-determining step. The C−C activation reaction was found to take place by two different routes; both proceed through the initial formation of the η2-arene complex 2. In one pathway, C−C activation takes place from an agostic C−H complex intermediate, and in the other, it occurs from the η2-arene complex directly. In both intermediates the C−C bond is predirected to the metal center. The methylene transfer reaction outcome is governed by thermodynamic factors. However, changing the thermodynamic factors might lead to the reverse methylene transfer reaction becoming kinetically accessible. The reverse reaction is relevant to the design of a potential catalytic methylene transfer system.

The Methylene-Transfer Reaction: Synthetic and Mechanistic Aspects of a Unique C−C Coupling and C−C Bond Activation Sequence

Oxidative addition of aryl iodides ArI (Ar = (a) C6H5, (b) C6H4CF3, (c) C6H3(CF3)2, (d) C6H4CH3, (e) C6H4OCH3), to the PCP-type complex Rh(PPh3)[CH2C6H(CH3)2(CH2PPh2)2] (1), yields the complexes Rh(Ar)[CH2C6H(CH3)2(CH2PPh2)2](I) (2a−e). Compounds 2a−e undergo intramolecular methylene transfer from the bis-chelating ligand to the incoming aryl under mild conditions (room temperature) giving Rh(CH2Ar)[C6H(CH3)2(CH2PPh2)2](I) (3a−e). The methylene transfer, which is a unique sequence of sp2−sp3 C−C bond reductive elimination and sp2−sp3 C−C bond activation, was investigated kinetically (reaction 2a → 3a), yielding the activation parameters ΔH⧧ = 17 ± 3 kcal/mol, ΔS⧧ = −23 ± 4 eu. The rate-determining step of this reaction is the C−C reductive elimination rather than the C−C activation step. X-ray structural analysis of 2a and 3b demonstrates that the Rh atom is located in the center of a square pyramid with the aryl (2a) and the benzyl (3b) trans to the vacant coordination site. Reaction of the complex Rh(CH...

Total Synthesis of the Furaquinocins

A viable synthetic route to the furaquinocin-class antibiotics is described. The key steps include (1) Co-complex mediated stereospecific 1,2-shift of an alkynyl group (9 → 6) to establish the C(2)−C(3) stereochemical relationship, (2) efficient construction of furanonaphthalene 20 from the sodium carboxylate derived from ester 19, and (3) stereoselective methylene transfer reaction to aldehyde 21 to establish the three contiguous stereogenic centers, C(2), C(3), and C(10). The stereodefined epoxide 23, thus obtained, served as a versatile intermediate in divergent syntheses of four congeners of this class of natural products, furaquinocins A (1a), B (1b), D (1d), and H (1h), by changing the vinylic nucleophiles.

The tropylium/benzylium ion dichotomy in the gas-phase reactions of transition metal chalcogenide cations with toluene

In the ion/molecule reactions of toluene with the transition metal chalcogenide cations FeO + and MoX n + (X  O, S; n = 2, 3), heterolytic CH bond activation leads, inter alia, to [C 7,H 7] + carbocations. Despite its high intrinsic reactivity, the iron oxide FeO + yields almost exclusively the benzylium ion. Deuterium labelling reveals that this process, as well as the subsequent methylene transfer reaction of the benzylium ion with toluene, to form xylenium ion and neutral benzene, hardly involves any H/D equilibration processes. Surprisingly, none of the transition metal chalcogenides under study gives rise to the formation of tropylium ion; rather, the energetically less stable benzylium ion is formed in the reactions of toluene with FeO + and MoX n + (X  O, S; n = 2, 3). Furthermore, the results suggest a re-interpretation of previous findings with respect to H/D equilibration in the reactions of labelled benzylium ions with toluene.

Cubylcarbinyl Cation: Fact or Fiction?

Ab initio molecular orbital calculations have been used to study the stability of the cubylcarbinyl cation (21). The secocubylcarbinyl cation (25) is the only minima found which resembles 21. Conversion of 25 to the homocubyl cation requires 174.6 kJ/mol. A barrier of 303.7 kJ/mol is calculated for ring expansion of cubylmethanol (7) to 1-homocubanol (13). Protonation of 7 forms the corresponding oxonium ion (30) which has a C−O bond similar to that found in protonated methanol. The oxonium ion formed by protonation of cubylmethanol (30) undergoes ring expansion to the 1-homocubanoxonium ion (32) with a barrier of only 4.0 kJ/mol. Density functional calculations predict a barrier-free reaction. The presence of the hydroxyl function in 7 directs the reaction toward ring expansion rather than ring opening through formation of the oxonium ion 30. A similar barrier reduction is observed in the methylene-transfer reaction in propanol (33) upon protonation.

ChemInform Abstract: Asymmetric Methylene Transfer Reactions. Part 2. Asymmetric Synthesis of Oxiranes form Carbonyl Compounds by Methylene Transfer Reaction Using Chiral S‐Neomenthyl and S‐exo‐2‐Bornyl Sulfoximines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Asymmetric methylene transfer reactions II: Asymmetric synthesis of oxiranes from carbonyl compounds by methylene transfer reaction using chiral S-neomenthyl and S-exo-2-bornyl sulfoximines

Abstract Three chiral sulfoximines, viz. , (1R,Ss)-(−)-S-methyl-S- exo -2-bornyl-N-tosyl sulfoximine, 9a , its epimer at sulfur, (1R,Rs)-(+)- 9b , and (1R,3S,4S,1′S,Rs)-(+)-S-methyl-S-neomenthyl-N-(camphor-10-sulfonyl) sulfoximine, 19 , were used as methylene transfer reagents in the preparation of nonracemic oxiranes (enantiomeric excess, 19–86%) from prochiral carbonyl compounds. Sulfoximines 9a and 9b were found to be less effective (ee, 19–68%) than the corresponding S-neomenthyl sulfoximines 2a and 2b (ee, 56–86%), and, sulfoximine 19 , despite having a chiral auxiliary on nitrogen in place of the tosyl group, was found to be only as effective as the corresponding N-tosyl sulfoximine 2b in influencing the steric course of these reactions. The absolute configuration at sulfur of all the synthesised sulfoxides and sulfoximines has been established by X-ray studies.

ChemInform Abstract: Asymmetric Methylene Transfer Reactions. Part 1. Asymmetric Synthesis of Oxiranes from Carbonyl Compounds by Methylene Transfer Reaction Using Chiral S‐Methyl‐S‐neomenthyl‐N‐tosyl Sulfoximines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Asymmetric methylene transfer reactions I: Asymmetric synthesis of oxiranes from carbonyl compounds by methylene transfer reaction using chiral S-methyl-S-neomenthyl-N-tosyl sulfoximines

The use of ylides prepared from (−)-S-methyl-S-neomenthyl-N-tosyl sulfoximine, 10a, and its epimer at sulfur, 10b, as methylene transfer reagents for the conversion of prochiral carbonyl compounds to oxiranes has yielded chiral oxiranes with 56–86% enantiomeric excess.

Gas phase substitution reactions by radical cations. Part 3. Methylene transfer of the CC ring-opened oxirane radical cation to pyrazole and imidazole

In the chemical ionization source of a mass spectrometer the CC ring-opened oxirane radical cation transfers a methylene group to imidazole and pyrazole. The structures of the [M + M] ṡ+ reaction product ions and those of the ionized methylpyrazole and methylimidazole isomers have been established by collisionally induced dissociation (CID) spectrometry. The methylene transfer reaction of oxirane to pyrazole and imidazole yields 1-methylene-2 H-pyrazolium and 1-methylene-3 H-imidazolium α-distonic radical cations, respectively. Their relative stabilities, and those of three other possible isomeric α-distonic product ions, have been calculated by ab initio methods at the #UHF/6-31G//3-21G level of theory.

252Cf plasma desorption mass spectrometry of some group 8 metal-containing coordination compounds

252 Cf plasma desorption mass spectrometry was applied to some series of ionic coordination compounds and was demonstrated to yield better results than fast atom bombardment mass spectrometry. Intra-ligand fragmentation was observed regularly, and evidence was also obtained for a fission fragment-induced methylene transfer reaction

Titanium-mediated methylene transfer reactions on sugar esters, lactones, and uloses

The titanium alkylidene 1, a versatile methylenating agent readily derived’ from the rather costly Tebbe compound 2, has been used in Wittig-type reactions to convert ketones into olefins and esters into vinyl ethers’. We now reportt its application to a variety of sugar derivatives that contain carbonyl and/or ester functions, with the aim of delineating the scope of the reaction with respect to blocking groups and the structure of the ketone, ester, or lactone. In order to simplify the procedure and increase the value of the method, the unpurified form of 2 was used (see Experimental). Pure, crystalline Tebbe reagent has been used by others3t4 on some aldonolactones and, where comparisons can be made, both similarities and differences were found. Reaction of the ulose 3 (X = 0) and the aldehyde 5 (R = H) with 2 gave, after chromatography, 70% and 35%, respectively, of the olefins 4’*(’ and 6 (R = H)7 in experiments that were easier to execute than the customary Wittig procedure5. Mono-esters of sugars were converted smoothly into vinyl ethers. Thus, 1,2:5,6di-0-isopropylidene-u-D-glucofuranose 3-acetate, 3-benzoate, and 3-p-chlorobenzoate gave, in good yields, the respective substituted vinyl ethers 7 (R = Me, or Ph, or ClC6H4). Each of the vinyl ethers 7 was susceptible to hydrolysis and gave methyl ketones uiu hemiacetals. The stability of these compounds towards hydrolysis increased in the order cited. Esters of glycuronic acids reacted readily with the crude 2, thereby affording a route to chain-extended sugars. The methyl glucoronate derivative 8 gave the methylene compound 9, and the methyl galacturonate derivative 5 (R = OMe) gave compound 6 (R = OMe), which needed more careful handling than 9 because it was rapidly hydrolysed on silica gel with neutral eluants to give the useful ketone 5 (R = Me). The &lactones 2,3,4,6-tetra-O-methyl-p-glucono-1,5-lactone (10, R = Me) and